Prostate cancer has evolved from a relatively common but infrequently discussed neoplasm to a major clinical entity with significant public health and economic ramifications. The wide-spread application of prostate-specific antigen (PSA) into clinical practice in the late 1980s has had a paradigm shifting impact on the management of prostate cancer. Among the most visible consequence of PSA-based screening is the substantial increase in the percentage of newly diagnosed patients who are felt to have clinically localized disease. This in turn has translated into a very significant increase in the number of patients undergoing curative-intent surgery and radiotherapy. Additional prostate cancer subsets have been created, including patients with PSA-only evidence of disease following curative-intent therapy (termed "biochemical failure") and patients with rising PSA values following hormonal therapy, termed "androgen-independent prostate cancer, biochemically defined."

It is estimated that there will have been 230,110 new prostate cancer diagnoses in 2004, with 29,900 men dying of the disease. Prostate cancer is the most commonly diagnosed neoplasm (excluding non-melanoma skin cancer), and it is the second most common cause of cancer death, after lung cancer, in American men. Worldwide, prostate cancer ranks third in cancer incidence and sixth in cancer mortality among men. There is, however, a significant disparity in incidence and mortality rates between world regions, with a very low incidence in China and Japan in contrast to the United States and parts of Western Europe. This wide variability in incidence is likely multifactorial with varying effects of genetic predisposition, diet, and other environmental factors and the widespread use of prostate cancer screening in the United States. Various autopsy studies have shown that histologic evidence of prostate cancer increases with age, and that roughly 70% to 80% of men older than 80 years will have some evidence of latent disease. It is this observation that has complicated the prostate cancer screening debate, with critics questioning the ability of screening to discriminate between clinically relevant disease and latent disease.

Risk Factors
The causes of prostate cancer remain poorly understood. The main predictors of prostate cancer risk are age, race, and family history. The incidence of prostate cancer in US men increases significantly above age 50 years. African American men have a higher incidence and prostate cancer-related death rate than do Caucasian men. Prostate cancer can be sporadic, hereditary, or familial, with the latter defined by a clustering of prostate cancer cases within members of a family. Men with either a father or brother diagnosed with prostate cancer are twice as likely to develop the disease than are men without affected relatives. In those families with two or three affected first-degree relatives, the risk of developing prostate cancer increases 5- to 11-fold.¹

There are numerous purported molecular, genetic, environmental, and dietary factors with varying degrees of supporting evidence. Recent work has provided compelling data to support the role of elevated serum testosterone and insulin growth factor-1 levels as significant risk factors.² Many candidate dietary components have been proposed to influence human prostatic carcinogenesis, including fat, calories, fruits and vegetables, antioxidants, and various micronutrients, but the specific role of dietary agents in promoting or preventing prostate cancer remains controversial.

The pathophysiology of prostate cancer is poorly understood and for many years was an underrepresented area of investigation, in contrast to work in colon and breast cancer. Over the past decade there has been a significant increase in focus on this neoplasm with a concomitant increase in funding for basic investigation. Among the challenges faced by investigators attempting to understand early steps in the carcinogenic pathway is the lack of a reliable animal model of prostate cancer.

High-grade prostatic intraepithelial neoplasia (PIN) is the histologic entity widely considered to be the most likely precursor of invasive prostate cancer. PIN is characterized by cellular proliferation within preexisting ducts and glands with cytologic changes that mimic cancer. PIN is associated with progressive abnormalities of phenotype and genotype that are intermediate between normal prostatic epithelium and cancer.³ The recognition of the strong association of high-grade PIN and cancer has led many investigators to propose its use as an intermediate marker in chemoprevention studies.

Over the past decade, recognition of a hereditary form of prostate cancer has prompted a vigorous research effort into the molecular genetics of prostate cancer, with various research teams performing linkage studies leading to the identification of several chromosomal loci that may be the source of prostate cancer susceptibility genes. At least six prostate cancer susceptibility loci have been identified to date, with increasing evidence that there is no single major gene accounting for a large proportion of susceptibility to the disease.⁴ The proportion of prostate cancer cases caused by mutations in these genes is estimated to be 5% to 10%, with the hereditary form of the disease diagnosed, on average, approximately 7 years earlier than the sporadic form of the disease.⁵

The clinical manifestations of prostate cancer result from the effects of local growth of the tumor, the spread to regional lymph nodes via the lymphatics, and the hematogenous dissemination to distant metastatic sites.

Although most patients with early-stage prostate cancer are asymptomatic, locally advanced disease may lead to obstructive or irritative voiding symptoms that result from local tumor growth into the urethra or bladder neck and/or by extension into the trigone of the bladder.

Prostate cancer most frequently spreads to bone, frequently leading to bone pain. A small but important subset of patients may develop spinal cord impingement from epidural spread of disease, resulting in pain and neurologic compromise that, depending on the location of the spinal lesion, could include the irreversible loss of bowel and bladder function and the ability to walk. Other common sites of metastatic spread include lymph nodes, with some patients presenting with progressive lymphedema and/or renal insufficiency as a consequence of obstruction of pelvic lymphatics and ureteral outlet obstruction.

With the introduction of PSA into clinical practice in the late 1980s and the subsequent influential recommendations of the American Urological Society and the American Cancer Society, prostate cancer screening (PSA plus digital rectal examination) has become widely used in the United States. Prostate cancer screening remains highly controversial (as evidenced by the wide array of screening recommendations, Table 1) as there is no prospective evidence demonstrating a decrease in prostate cancer-specific mortality.^6,7

Several prospective screening trials are ongoing in the United States and around the world. Among the largest are the European Randomised Screening for Prostate Cancer (ERSPC) trial, which has accrued over 160,000 men, and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) sponsored by the National Cancer Institute, which completed enrollment of more than 154,000 participants, including 75,000 men, in the summer of 2001. It is hoped that the results of these trials (anticipated sometime after 2004) may provide more definitive guidance to patients and clinicians about the impact of screening. Until more definitive data are available, many of the major medical societies recommend a careful discussion with individual patients, prior to screening, regarding the potential risks and benefits.⁸ Patients with significant comorbid conditions and those with life expectancies of less than 10 years are far less likely to benefit from therapeutic intervention and therefore should not be considered for screening. Alternatively, patients at potentially high risk, eg, African Americans and those with one or more affected first-degree relatives, might be appropriate candidates for screening at an earlier age (40 to 50 years).

Over the last decade, the penetration of PSA-based screening has caused a stage migration, with an increasing proportion of patients with normal rectal examination findings being diagnosed on the basis of an elevated PSA (clinical stage T1c in the TNM staging classification). There has also been a concomitant decrease in the number of patients who present initially with evidence of metastatic disease.

Following a biopsy-proven diagnosis of prostate cancer, patients are clinically staged using the TNM system (Table 2) based upon the extent of local tumor on rectal examination and the presence or absence of metastatic disease. In the last several years a series of outcomes-based nomograms (http://prostate.urol.jhu.edu/Partin_tables/) have been developed to improve the clinician's ability to predict the patient's pathologic stage, which ultimately represents the best long-term outcome measure. The ability to predict pathologic stage with greater accuracy allows more appropriate initial treatment selection. These nomograms use clinically available parameters such as PSA, Gleason scores obtained from prostate biopsies, and the estimated clinical stage.⁹

TREATMENT AND OUTCOMES

Chemoprevention:

Finasteride, an inhibitor of 5a-reductase, has been widely used to treat symptoms related to benign prostatic hyperplasia. A large randomized trial (over 18,000 participants) comparing finasteride to placebo demonstrated a 25% decrease in the prevalence of prostate cancer over a seven year period for men taking finasteride. Of note, however, was the finding that tumors of Gleason grade 7-9 and 10 were more common in patients receiving finasteride.¹⁰

Localized Prostate Cancer:

For appropriately selected patients with clinically organ-confined prostate cancer, potential curative approaches include radical prostatectomy and radiation therapy. The optimal treatment for localized prostate cancer remains undefined in part because of the absence of prospective randomized clinical trials comparing outcomes of surgery and radiotherapy. Other factors that complicate our understanding of the impact of these therapies include the stage migration resulting from screening and the long natural history of localized prostate cancer. Using biochemical failure (PSA recurrence following radical prostatectomy or three consecutive rising PSA levels after a nadir in patients receiving radiotherapy) as an intermediate end point and after adjustment for stage and grade of tumors, outcomes with external beam radiotherapy and radical prostatectomy at 8 years follow-up are equivalent.¹¹

Among the challenges in identifying the most beneficial therapy for localized disease is the relatively rapid evolution of radiotherapy techniques over time. Over the last 5 to 10 years, there has been increasing evidence of a dose-response relationship for prostate cancer, leading to an increase in conventional radiotherapy dosages for localized disease from the upper 60-Gy range to current dosages of 72 to 78 Gy. This increase in dosage has been made possible by technologic improvements in radiotherapy delivery systems using three-dimensional conformal techniques (computer-guided dosing techniques that attempt to minimize radiation dosage outside of the target field) such as intensity-modulated radiotherapy.¹² Recent evidence from prospective randomized clinical trials has also demonstrated that, for selected patients at high risk, a survival benefit is associated with androgen deprivation used in conjunction with external beam radiotherapy.¹³

Prostate brachytherapy (using I 125 or Pd 103) has increasingly been used in the management of appropriately selected patients opting for radiotherapy.¹⁴ Compared with external beam radiotherapy, it has some important patient advantages that include a single outpatient treatment versus the typical 7-week course of external beam treatment. Its ultimate utility compared with radical prostatectomy is being tested in a prospective randomized trial conducted under the auspices of the American College of Surgeons and the National Cancer Institute.

Given the lack of definitive evidence of the optimal therapy for localized prostate cancer, an important consideration for patients and the physicians helping guide their decision is the potential side effects of radiotherapy and surgery. The major side effects of therapy for localized prostate cancer affect urinary, bowel, and sexual functions. Although, historically, reports of these side effects in the literature were typically those reported to the treating physicians in retrospective reviews, recently there has been a large effort by numerous investigators using "modern" quality of life assessment tools to better quantitate the impact of local therapies on long-term quality of life.¹⁵ These assessments should be used by patients and physicians to help guide treatment decisions.¹⁶

Metastatic Prostate Cancer:

Hormonal therapy (androgen ablation) has for more than 60 years been the primary initial treatment of patients with metastatic prostate cancer. Androgen ablation options for patients with advanced prostate cancer include bilateral orchiectomy, luteinizing hormone-releasing hormone (LHRH) analogs, and combined androgen blockade (combination of either orchiectomy or LHRH analog plus an antiandrogen). Although orchiectomy remains the historical gold standard, LHRH therapy is equivalent therapeutically, and patients are increasingly opting for medical therapy in part because of the psychological implications of surgical castration. Orchiectomy remains the treatment of choice for patients presenting with spinal cord compression or diffuse, painful bone metastases, as it leads to the rapid achievement of castrate levels of testosterone (hours) compared with the 14 to 21 days required for LHRH analogs.

In human males, 5% to 10% of circulating testosterone originates from conversion of adrenal steroid precursors. Nonsteroidal antiandrogens act at the level of the androgen receptor to inhibit the stimulatory effects of testosterone. The use of an antiandrogen in addition to either LHRH or orchiectomy is referred to as "combined androgen blockade." The role of combined androgen blockade remains controversial, with the preponderance of evidence against its routine use.¹⁷ However, approximately 10% of patients started on LHRH therapy will have an initial testosterone flair, which can be obviated by a 30-day course of an antiandrogen started concomitantly with LHRH therapy.

Unfortunately, the vast majority of patients with metastatic prostate cancer will evidence disease progression on hormonal therapy (median response duration to hormonal therapy is 24 to 36 months). Patients with advanced prostate cancer typically have progressive bone pain and cancer cachexia. Significant anemia is common, although transfusion dependency is rare. Some patients with primarily nodal involvement may develop significant lymphedema or ureteral obstruction. Spinal cord compression is relatively common, and a high index of suspicion must be maintained for patients presenting with back pain even in the absence of neurologic findings.

Historically, management of advanced disease consisted of second-line hormonal therapies and palliative radiotherapy. The latter remains an important component of patient management. Over the past decade, there has been compelling evidence that chemotherapy has the potential to provide meaningful palliation in selected patients, with improvement in pain and other disease-related symptoms.¹⁸ Two recently reported phase III trials of chemotherapy in patients with advanced prostate cancer has provided evidence that docetaxel-based chemotherapy can provide a modest improvement in survival.^19,20 There has been recent evidence, similar to findings in breast cancer and multiple myeloma, that bisphosphonate therapy with toledronate can decrease skeletal progression rates and complications in patients with androgen-independent metastatic bone disease. Aggressive pain and symptom management with appropriate use of opioids and palliative radiotherapy is essential to the optimal management of patients with progressive disease.

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